The long-term objectives of this research program are to use newly found immunological mutants of the mouse to investigate the etiology of immunodeficiency and autoimmune diseases and to ascertain the role of the immune system in the development of spontaneous neoplasms. The main objectives of the current project are to determine the underlying cellular and biochemical basis for development and immunological defects, polyclonal B-cell activation, and pathologic abnormalities in motheaten (me/me) and viable motheaten (mev/mev) mice. Homozygosity for these deleterious alleles at the motheaten locus causes the most severe, genetically determined immunologic dysregulation known in mice. The specific aims include: (1) evaluation of the effects of depleting B cells or T cells in vivo on immunopathologic states; (2) determination of the roles of soluble lymphokines in the induction of B-cell differentiation in normal resting B cells and in B cell tumor lines; (3) analysis of parameters of macrophage activation; (4) evaluation of the role of Ia antigen expression on inappropriate cellular interactions; and (5) assessment of the mechanism of pulmonary injury in irradiated recipients of bone marrow cells from me/me mice. These studies will contribute to an understanding of complex immunologic diseases of genetic origin and increase our knowledge about the immune system in normal and pathologic states. (SR)